- PHARMACEUTICAL COMPOSITION FOR INHIBITING THE TRANSCRIPTION FACTOR INDUCIBLE BY HYPOXIA, MODULATORS OF PATHOLOGICAL PROCESSES OF ANGIOGENESIS, ONCOGENESIS, INFLAMMATION, APOPTOSIS, AND CELLULAR THERAPY
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The present invention is included in the field of pharmacology and medical chemistry and relates to novel molecules represented by general formula (I), especially the one called FM19G11, as well as to pharmaceutical compositions containing them. Said pharmacologically optimized compositions are capable of modulating and/or inhibiting the transcription of genes modulated by the hypoxia-inducible transcription factor (HIF) and which are directly and/or indirectly involved in pathological processes related to cancer, inflammation, tissue repair, stem cell differentiation and regenerative therapy. The present invention also relates to a method for the synthesis of said molecules (I) and to the use thereof in the manufacture of a medicament for the treatment of the mentioned pathological processes.
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- FM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status
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The biology of the a subunits of hypoxia-inducible factors (HIFα) has expanded from their role in angiogenesis to their current position in the self-renewal and differentiation of stem cells. The results reported in this article show the discovery of FM19G11, a novel chemical entity that inhibits HIFα proteins that repress target genes of the two α subunits, in various tumor cell lines as well as in adult and embryonic stem cell models from rodents and humans, respectively. FM19G11 inhibits at nanomolar range the transcriptional and protein expression of Oct4, Sox2, Nanog, and Tgf-α undifferentiating factors, in adult rat and human embryonic stem cells, FM19G11 activity occurs in ependymal progenitor stem cells from rats (epSPC), a cell model reported for spinal cord regeneration, which allows the progression of oligodendrocyte cell differentiation in a hypoxic environment, has created interest in its characterization for pharmacological research. Experiments using small interfering RNA showed a significant depletion in Sox2 protein only in the case of HIF2α silencing, but not in HIF1α-mediated ablation. Moreover, chromatin immunoprecipitation data, together with the significant presence of functional hypoxia response element consensus sequences in the promoter region of Sox2, strongly validated that this factor behaves as a target gene of HIF2α in epSPCs. FM19G11 causes a reduction of overall histone acetylation with significant repression of p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation. Arrays carried out in the presence and absence of the inhibitor showed the predominant involvement of epigenetic-associated events mediated by the drug.
- Moreno-Manzano, Victoria,Rodriguez-Jimenez, Francisco J.,Acena-Bonilla, Jose L.,Fustero-Lardies, Santos,Erceg, Slaven,Dopazo, Joaquin,Montaner, David,Stojkovic, Miodrag,Sanchez-Puelles, Jose M.
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p. 1333 - 1342
(2010/12/18)
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